THE NARCOTIC ANALGESICS Narcotics block the transmission of the nerve signal across nerve gaps, [the minor analgesics blocked prostaglandin synthesis] The more important ones: Morphine, codeine, oxycodone (PERCODAN), hydromorphone (DILAUDID), methadone, + heroin [ = not legal] meperidine (DEMEROL), pentazocine (TALWIN), fentanyl (SUBLIMAZE), buprenorphine (BUPRENEX),

Morphine: Opium [est. ~ 10,000 tons] extracted from the poppy Papaver somniferum, Afghanistan estimated 92% of supply. Currently a glut, Afghan farm price $150/kg!!!, 2$/mg here

contains about 10% morphine, can be recrystallized as white morphine sulfate (first pure form in about 1803) Used orally (LAUDANUM) before 1856 when syringe was invented

Normal dose to kill pain: 5-10mg injected analgesic - kills pain constipator - anti-dysentery side effect narcotic - induces drowsiness, lethargy DEPRESSES RESPIRATORY SYSTEM usual overdose effect some euphoria - addictive

Morphine binds to opiate receptors that control passage of Ca2+ and K+ through channels which in turn control acetylcholine (nerve transmitter) flow across synapses

Codeine (½% of opium), made synthetically (60,000 kg/y USA); only about 10% of pain relief of morphine, though better cough suppressant Legal OTC if < 2.2 mg/mL or in combination with aspirin or Tylenol, Egs. 222, 292; Tylenol 1 (8mg); Tylenol 2 (16mg), Tylenol 3 (30 mg)

HEROIN Bayer labs (1874): sold soluble HCl salt as 'cough syrup' H itself has mp 173oC, white, bitter taste H.HCl salt has mp 243-244oC H passes the blood-brain barrier faster (bigger rush) than morphine (more fat like) BUT IS BROKEN DOWN TO MORPHINE in brain for use Street H typically used to be 1-13% pure, now some batches much more pure

OPIATES narcotics - induce drowsiness insomnia, irritability constrict pupil of eye (pin-point pupils) depress respiration (overdose danger) reduce bowel activity - constipation diarrhea reduce all secretions (gastric, bile) chills, cramps,nausea Timing of effects: 8-12h runny nose, eyes, sweating 12-16h insomnia 16-48h loss of appetite, nausea, vomiting, diarrhea, irritability 48-72h tremors, sneezing, chills, flushes, ejaculation/orgasm, abnormal white cell counts

Opiates CROSS TOLERATE, so need larger doses (increased enzyme production) injection at any point suppresses symptoms HENCE ADDICTION: at $2/mg most addicts need >2 fixes (10-20mg x 2)per day, expensive Even in hospitals, patients on longer term morphine build up a tolerance Recent Queen’s U study suggests small injection of the antagonist naloxone returns sensitivity to the drug

NATURAL PAIN KILLERS in body are pentapeptides (small proteins, 5 amino acids long) called ENKEPALINS Methionine enkepalin = Tyr-Gly-Gly-Phe-Met Leucine enkepalin = Tyr-Gly-Gly-Phe-Leu these are often part of larger proteins, eg. b-endorphin contains 31 amino acids, first 5 of which are shown above (Met) NEUREX Corp. has developed SNX-111, a 26-peptide which is injected spinally to block Ca channels in spinal cord, available now as ZICONOTIDE (US).

HYDROMORPHINONE (hydromorphone, DILAUDID) SYNTHETIC OPIATES Vicodin HYDROMORPHINONE (hydromorphone, DILAUDID) 5-7x more potent than morphine so 1.5 - 2 mg equivalent to 10 mg morphine, but lasts a little less, only 2-4 h: used in Victoria for cancer patients – pills can be ground and injected for high ($50/street).

Hydrocodone = Vicodin Hycodan in Canada as an antitussive (cough) 5mg

OXYMORPHONE (NUMORPHAN) 1.5 mg equivalent to 10 mg morphine, lasts 3-6 h 2003 - extended release version did not work well, caused many addictions, lawsuits in US

DEMEROL (1930's) 15% of morphine's effectiveness Pethidine DEMEROL (1930's) 15% of morphine's effectiveness dose 50-150mg/4h (up to 75mg if by i.v.) NO nausea, no affect on pupils CAUSES sedation, euphoria and is addictive MORPHINE AGONIST, goes to same receptor sites

Newer synthetic “opioids” Butorphanol Nalbuphine Stadol, Torbutrol long used by vets Nubain – Oct 2006 Canada (Sandoz) 2 mg injected 10 mg injected both are mixed agonist/antagonist (against different receptors)

METHADONE equally potent to morphine or heroin; highly addictive 08: >250,000 users of methadone METHADONE equally potent to morphine or heroin; highly addictive orally NO sedation or sleepiness (addict can hold a job), STOPS Withdrawal symptoms, blocks action of heroin only need one dose per day if oral (30-120 mg)(slower acting), cheap 10 cents per dose Best supplied in orange juice, since if injected can get rush ($1/mg on street for powder) Addicts claim harder to get off methadone than heroin

Propoxyphene DARVON 50mg is equiv to 10 mg morphine, sold in 100mg oral capsules, somewhat addictive overdoses kill 1000-2000 per year in USA by respiratory depression PHYSICIAN WARNING: do not prescribe to suicidal patients, MAX 600mg/day 800-1200mg dose causes convulsions.

THE FENTANYLS - DESIGNER DRUGS R1 R2 R3 Name H H H fentanyl Me H H 3-Me-fentanyl H H F p-F-fentanyl H Me H a-Me-fentanyl Fentanyl (SUBLIMAZE) ~150 x morphine, used in major surgery 2-3mg/kg, DOSE 0.1-0.2 mg injected very short acting, very addictive illegal ones ~10 x more active

Sufentanil Alfentanil “Sufenta” “Alfenta” Newer, legal ones: Sufentanil Alfentanil “Sufenta” “Alfenta” Dose 0.01-0.04 mg 0.4-0.8 mg injected

RUSSIA - OCT 23 2002 - Chechen terrorists took ~ 800 people hostage in a Moscow theater Russia pumped fentanyl gas thru ventilation system on day 3, but refused to identify gas to local medics 130 people died, Russian military lost no one. Antidote = Naloxone!! 3-Me-fentanyl: ~3000 x morphine - overdoses easy, death

A DRUG GONE WRONG In 1980's, MPPP was a popular, easy to make-at-home drug Ca. 25x stronger than Demerol (CO2Et compd) Poor batch control led to ester elimination to give MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Several hospitals reported patients suffering from rigidity and Parkinson’s-like symptoms All had taken ‘street heroin’ that was in fact MPTP

Crosses into brain, kills dopamine producing cells, induces tremors, rigidity, loss of muscle control, i.e. PARKINSON's symptoms [Nov. 2005 Can. Chem. News] Barry Kidston, U. Maryland grad student First synthesized MPPP and injected himself; after several months, he brewed a bad batch, and was hospitalized, eventually the doctors tried L-DOPA which improved his fate – for 2 yrs, until he died of an overdose of cocaine!

ANTAGONISTS FOR HEROIN Inject Oral [oxymorphone with new R groups] NARCAN = Naloxone.HCl 0.4 - 2 mg injected, repeat in 3 min if nec. is best antidote for heroin overdose [no overdoses of naloxone recorded]

BLOCKS action of heroin, no narcotic activity, no respiratory depression prevents addicts getting high (pregnant mothers....) Methenex = methadone + naloxone = no rush ReVia = Naltrexone.HCl = ORAL, 50mg/day for 3 days, or one 150 mg dose

THE AZOCINES - mixed agonist-antagonists Pentazocine = TALWIN ~60mg injected dose or ~180mg oral dose is equiv to 10mg injected morphine blocks euphoric effect of morphine, but less respiratory depression

injected oral Sufentanil 0.01-0.04 - Fentanyl 0.1-0.2 - EQUIVALENT DOSES to 10 mg morphine injected injected oral Sufentanil 0.01-0.04 - Fentanyl 0.1-0.2 - Alfentanil 0.4-0.8 - Oxymorphone 1.5 - Hydromorphone 2 4-6 Butorphanol 2 - Morphine 10 20-30 Nalbuphine 10 - Oxycodone - 30 Propoxyphene 50 100 Pentazocine 60 180 Meperidine 75 300 Codeine 120 200

VIGABATRIN ‘V’ SABRIL (Aventis) [an anti-epilepsy drug in Canada] reduces the effect of heroin, methamphetamine, alcohol V is an inhibitor of GABA transaminase, the enzyme which breaks GABA down If GABA is high, less dopamine (the brain exciting amine) is produced GABA Vigabatrin g-aminobutyric acid